Design, synthesis and pharmacological evaluation of 3-spiro[benzofuran-2,4'-piperidine] IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma.

Interleukin-1 receptor-associated kinase 4 (IRAK4) has emerged as a promising target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein, we report the identification and structure-activity relationship studies of a new series of 3-spiro[benzofuran-2,4'-piperidine] IRAK4 inhibitors designed to improve the pharmacokinetic properties of a previously identified series. The representative compound 13 showed strong inhibitory activity against IRAK4, significant antiproliferative effect against DLBCL cells, and improved pharmacokinetic properties. In addition, compound 13 effectively inhibited the activation of IRAK4 signaling pathway and induced DLBCL cell apoptosis. These results indicated that compound 13 was a promising lead compound for the development of anti-DLBCL agents.